Publications by authors named "Joydeep Ghosh"

79 Publications

Multimodality treatment outcome in patients with primary malignant mediastinal germ cell tumor in adults.

Cancer Rep (Hoboken) 2021 Feb 8;4(1):e1306. Epub 2020 Oct 8.

Department of Radiodiagnosis, Tata Medical Center, Kolkata, India.

Background: Malignant mediastinal germ cell tumor (MGCT) is rare and has poor outcomes even after multimodality treatment. Data from resource-poor countries are scarce in the literature.

Aims: To evaluate the clinicopathologic features and treatment outcome of primary malignant MGCT at our center.

Methods And Results: Single institutional data review of patients aged ≥18 years, treated with a diagnosis of malignant MGCT between Nov'2013 and Nov'2019. Risk stratification was done as per International Germ Cell Cancer Collaborative Group (IGCCCG) classification. Patients were treated with platinum based chemotherapy and surgical resection for the residual disease was performed in non-seminomatous histology.28 patients had MGCT with a median age of 25 years (range:18-36) and all were male. Seven patients had superior vena cava obstruction (SVCO) at diagnosis and pre-treatment histological diagnosis was available in 23 (82%) patients. Seven (25%) patients had seminoma histology, all were of good risk as per IGCCCG risk criteria, whereas others had non-seminoma histology with poor-risk group. Seven patients with seminoma histology achieved a complete response after initial treatment. Six patients with non-seminoma histology underwent complete resection of residual disease post-chemotherapy and five revealed residual viable tumors. After a median follow-up of 10.8 months (range:2.9-75), 3-year progression-free survival (PFS) and overall survival (OS) estimate was 61.2% and 94.7% in the whole cohort, respectively and 3-year PFS and OS estimate was 100% in patients with seminoma histology.

Conclusions: This is the largest data set of MGCT patients' outcomes reported from India with multi-modality treatment. All patients were male and one-fourth had SVCO at presentation. Seminoma histology patients had a 100% outcome after initial platinum based chemotherapy. But, those with non-seminoma histology had a poor outcome even with chemotherapy and surgery.
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http://dx.doi.org/10.1002/cnr2.1306DOI Listing
February 2021

Megakaryocytes promote osteoclastogenesis in aging.

Aging (Albany NY) 2020 07 7;12(14):15121-15133. Epub 2020 Jul 7.

Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN 46202, USA.

Megakaryocytes (MKs) support bone formation by stimulating osteoblasts (OBs) and inhibiting osteoclasts (OCs). Aging results in higher bone resorption, leading to bone loss. Whereas previous studies showed the effects of aging on MK-mediated bone formation, the effects of aging on MK-mediated OC formation is poorly understood. Here we examined the effect of thrombopoietin (TPO) and MK-derived conditioned media (CM) from young (3-4 months) and aged (22-25 months) mice on OC precursors. Our findings showed that aging significantly increased OC formation in vitro. Moreover, the expression of the TPO receptor, Mpl, and circulating TPO levels were elevated in the bone marrow cavity. We previously showed that MKs from young mice secrete factors that inhibit OC differentiation. However, rather than inhibiting OC development, we found that MKs from aged mice promote OC formation. Interestingly, these age-related changes in MK functionality were only observed using female MKs, potentially implicating the sex steroid, estrogen, in signaling. Further, RANKL expression was highly elevated in aged MKs suggesting MK-derived RANKL signaling may promote osteoclastogenesis in aging. Taken together, these data suggest that modulation in TPO-Mpl expression in bone marrow and age-related changes in the MK secretome promote osteoclastogenesis to impact skeletal aging.
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http://dx.doi.org/10.18632/aging.103595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425434PMC
July 2020

Perspective of Oncology Patients During COVID-19 Pandemic: A Prospective Observational Study From India.

JCO Glob Oncol 2020 06;6:844-851

Department of Medical Oncology, Tata Medical Center, Kolkata, West Bengal, India.

Purpose: The coronavirus disease 2019 (COVID-19) pandemic has imposed a unique challenge to oncology patients and their treatment. There is no study related to the patients' preference for systemic therapy during this pandemic. We have conducted a prospective study to analyze that aspect.

Methods: All consecutive patients who visited during the lockdown period from April 1-10, 2020, for systemic chemotherapy were included in the study for a questionnaire-based survey to evaluate the willingness to continue chemotherapy during this pandemic and factors influencing the decisions.

Results: A total of 302 patients were included (median age, 56 years; range, 21-77 years). Most common sites of cancer were breast (n = 114), lung (n = 44), ovary (n = 34), and colon (n = 20). Home address was within the city for 125 patients (42%), outside the city for 138 (46%), and outside the state for 37 (12%). Treatment was curative in 150 patients and palliative in 152. Educational status was primary and above for 231 patients and no formal schooling for 71. A total of 203 patients wanted to continue chemotherapy, 40 wanted to defer, and 56 wanted the physician to decide. Knowledge about COVID-19 strongly correlated with intent of treatment ( = .01), disease status ( = .02), knowledge about immunosuppression ( < .001), home location ( = .02), and education status ( = .003). The worry about catching SARS-CoV-2 was high in those with controlled disease ( = .06) and knowledge about immunosuppression ( = .02). Worry about disease progression was more with palliative intent ( < .001).

Conclusion: This study shows that oncology patients in our country are more worried about disease progression than the SARS-CoV-2 and wish to continue chemotherapy during this pandemic. The treatment guidelines in the COVID-19 scenario should incorporate patients' perspectives.
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http://dx.doi.org/10.1200/GO.20.00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328097PMC
June 2020

Real world experience of treatment and outcome in ALK-rearranged metastatic nonsmall cell lung cancer: A multicenter study from India.

Curr Probl Cancer 2020 06 17;44(3):100571. Epub 2020 Mar 17.

Tata Medical Center, Kolkata, India. Electronic address:

Background: Anaplastic lymphoma kinase (ALK) rearranged metastatic non-small cell lung cancer (NSCLC) comprises 5%-7% of all lung cancer and carries a good prognosis with available ALK-inhibitors. Majority of registration trials in ALK-inhibitors did not include Indian patients. Hence, this study was planned to analyze the outcome of Indian patients treated with ALK-inhibitors and associated challenges.

Methods: This is a multi-center study in 5 major tertiary care cancer centers across India treating ALK-rearranged NSCLC patients from April 2013 to April 2019. ALK rearrangement was determined by Ventana immunohistochemistry with D5F3 clone and/or by break-apart FISH. Patients treated with ALK-inhibitors in any lines of treatment were included in this study. Patients were evaluated for clinicopathologic features, patterns of ALK-inhibitors use and outcome. Progression free-survival (PFS) and overall survival (OS) were calculated and data were censored on April 30, 2019.

Results: A total of 274 patients were studied, out of which 250 patients received ALK inhibitor and were analyzed further for outcome. The median age was 50 years (range: 24-82) and male to female ratio of 1.17:1. ALK was evaluated by immunohistochemistry in majority of patients (97%), 3 patients by FISH and 3 more patients were evaluated by both methods. Sixty-five percent (n = 162) of the patients received ALK-inhibitor as first line therapy, 51 patients received ALK-inhibitor as switch maintenance therapy after initial chemotherapy. Crizotinib and Ceritinib were used in 88% and 12%, respectively. One patient received Alectinib. Forty-one percent of patients had CNS progression. After median follow up of 27 months (1-72 months), the median OS was 24.7 months with OS rate of 72%, 51%, and 18% at 1, 2, and 4-years respectively. Median OS was 21.2, 26, and 38 months in the first line ALK-inhibitors use (n = 162), switch maintenance group (n = 51) and second line ALK-inhibitors use (postchemotherapy progression) (n = 33), respectively. No baseline variable predicted PFS. Presence of brain metastasis (P = 0.039) and first line ALK-inhibitors use (P = 0.032) emerged as poor prognostic factor for OS on multivariate analysis. PFS rate was 70%, 47%, and 31% at 6, 12, and 18 months respectively.

Conclusion: This is one of the largest real-world data on outcome of ALK inhibitors in ALK-rearranged NSCLC from Asia. In absence of second line ALK inhibitor, initial chemotherapy followed by ALK-inhibitors (switch maintenance) had better outcome. This fact may be studied in individual patient data meta-analysis. Poor performance status and brain metastases at presentation are poor prognostic factors for overall survival. Second-line ALK inhibitor use crucial for better outcome and access to clinical trials are much needed in Indian patients.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100571DOI Listing
June 2020

Utility and safety of maintenance chemotherapy in advanced non-small cell lung cancer across various performance status categories: real-world experience.

Curr Probl Cancer 2020 06 5;44(3):100565. Epub 2020 Mar 5.

Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Electronic address:

Maintenance chemotherapy (MC) with pemetrexed is a commonly used strategy in nonsquamous non-small cell lung cancer. However, most of the available evidence is from subjects with good performance status (PS), while data on the real-world utility and safety of this strategy in subjects with various categories of PS is limited. We performed a retrospective analysis of multicentric data of 3 centers from India. All patients with advanced nonsquamous non-small cell lung cancer who received MC with pemetrexed after induction chemotherapy were included. Subjects were divided into 2 groups based on baseline Eastern Cooperative Oncology Group score before initiation of induction chemotherapy as good PS (<2) and poor PS (≥2). Progression-free survival, overall survival, and toxicity were assessed in the study population. A total of 290 subjects were included in the study, of whom a significant proportion (n = 104, 35.9%) had poor PS. Survival was better in subjects with good PS as compared to those with poor PS (1-year progression-free survival: 43.5% vs 29.8%, P = 0.021; 1-year overall survival: 61.8% vs 48.1%, P = 0.023). Grade 3/4 toxicity was observed in 14.5% of subjects during MC and was not different between both groups (P = 0.287). Renal dysfunction was more common in subjects who received ≥10 cycles of MC (10.7% vs 4.2%, P = 0.040). MC with pemetrexed appeared to be beneficial and safe in the real-world setting regardless of the baseline PS. However, survival benefit was more pronounced in subjects with good PS at baseline. Renal dysfunction was more frequently encountered in subjects who received prolonged MC.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100565DOI Listing
June 2020

Clinicopathological characteristics and treatment outcome in small cell lung cancer: A single institutional experience from India.

Lung India 2020 Mar-Apr;37(2):134-139

Department of Medical Oncology, Tata Medical Center, Kolkata, West Bengal, India.

Background And Objectives: Small cell lung cancer (SCLC) constitutes 14%-20% of all lung cancers. Clinical data on SCLC are scarce in literature. To report clinical features and treatment outcome of SCLC treated at our center.

Materials And Methods: This is a single institutional data review of SCLC patients treated between June 2011 and December 2018. Patients were staged as either localized or extensive disease after appropriate staging work-up. Patients with localized disease were treated with concurrent chemoradiation with platinum-based chemotherapy. Those with extensive disease were treated with platinum based palliative chemotherapy. Clinicopathological characteristics, treatment details, and outcome were recorded in this study. Patients who received at least one cycle of chemotherapy were included for survival analysis as intent-to-treat analysis.

Results: A total of 181 were patients registered with a median age of 62 years (range: 35-86 years) and male: female ratio of 166:15. Eighty-seven percent (n = 157) of patients had smoking history and 15% (n = 28) of patients had symptom of superior vena cava obstruction at baseline. Twenty-seven (15%) patients had localized disease at presentation. One hundred and twenty (66%) patients took systemic chemotherapy. Chemotherapy regimen was carboplatin only in 9 (7%), etoposide-carboplatin in 54 (45%), and cisplatin-etoposide in 57 (48%). Patients received median cycle number of 6 (range: 1-6). Of the evaluable 87 (73%) patients, initial response was complete response in 4, partial response in 57, stable disease in 20, and progressive disease in 6. Twenty patients received second-line chemotherapy at time of disease progression. After a median follow-up of 8.8 months (range: 0.3-46.1), median progression-free survival (PFS) of the whole population was 9.3 months.

Conclusions: Small cell carcinoma in our series had a high incidence of advanced stage (85%) and 13% of patients were nonsmoker. Only 66% of patients received palliative chemotherapy and achieved high disease control rate (>75%) in the evaluable patients with median PFS of 9.3 months.
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http://dx.doi.org/10.4103/lungindia.lungindia_370_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065549PMC
February 2020

Aging negatively impacts the ability of megakaryocytes to stimulate osteoblast proliferation and bone mass.

Bone 2019 10 9;127:452-459. Epub 2019 Jul 9.

Indiana University School of Medicine, Indiana, USA. Electronic address:

Osteoblast number and activity decreases with aging, contributing to the age-associated decline of bone mass, but the mechanisms underlying changes in osteoblast activity are not well understood. Here, we show that the age-associated bone loss critically depends on impairment of the ability of megakaryocytes (MKs) to support osteoblast proliferation. Co-culture of osteoblast precursors with young MKs is known to increase osteoblast proliferation and bone formation. However, co-culture of osteoblast precursors with aged MKs resulted in significantly fewer osteoblasts compared to co-culture with young MKs, and this was associated with the downregulation of transforming growth factor beta. In addition, the ability of MKs to increase bone mass was attenuated during aging as transplantation of GATA1 hematopoietic donor cells (which have elevated MKs/MK precursors) from young mice resulted in an increase in bone mass of recipient mice compared to transplantation of young wild-type donor cells, whereas transplantation of GATA1 donor cells from old mice failed to enhance bone mass in recipient mice compared to transplantation of old wild-type donor cells. These findings suggest that the preservation or restoration of the MK-mediated induction of osteoblast proliferation during aging may hold the potential to prevent age-associated bone loss and resulting fractures.
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http://dx.doi.org/10.1016/j.bone.2019.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708771PMC
October 2019

Axillary Lymph Node Metastasis in Gallbladder Carcinoma with Incidentally Detected Coexistence of Aberrant Right Subclavian Artery with Left-Sided Superior Vena Cava.

Indian J Nucl Med 2019 Jul-Sep;34(3):244-246

Department of Medical Oncology Tata Medical Center, Kolkata, West Bengal, India.

The sequential development of port site recurrence, followed by recurrence in the axillary lymph node in gallbladder carcinoma is very infrequently reported in the literature. The representing 18F-fluorodeoxyglucose positron emission tomography-computed tomography image shows a metastatic right axillary lymph node in a case of gallbladder cancer developed following surgical removal of port site recurrence and six cycles of chemotherapy. The image also shows coexistence of two incidentally detected vascular anomalies, i.e., aberrant right subclavian artery and left-sided superior vena cava. Coexistence of both the vascular anomalies is rare among the general population and have their own clinical implications as described.
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http://dx.doi.org/10.4103/ijnm.IJNM_62_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593955PMC
July 2019

CD166 Engagement Augments Mouse and Human Hematopoietic Progenitor Function via Activation of Stemness and Cell Cycle Pathways.

Stem Cells 2019 10 14;37(10):1319-1330. Epub 2019 Aug 14.

Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Hematopoietic stem (HSC) and progenitor (HPC) cells are regulated by interacting signals and cellular and noncellular elements of the hematopoietic niche. We previously showed that CD166 is a functional marker of murine and human HSC and of cellular components of the murine niche. Selection of murine CD166 engrafting HSC enriched for marrow repopulating cells. Here, we demonstrate that CD166-CD166 homophilic interactions enhance generation of murine and human HPC in vitro and augment hematopoietic function of these cells. Interactions between cultured CD166 Lineage Sca-1 c-Kit (LSK) cells and CD166 osteoblasts (OBs) significantly enhanced the expansion of colony-forming units (CFUs). Interactions between CD166 LSK cells and immobilized CD166 protein generated more CFU in short-term cultures than between these cells and bovine serum albumin (BSA) or in cultures initiated with CD166 LSK cells. Similar results were obtained when LSK cells from wildtype (WT) or CD166 knockout (KO) (CD166 ) mice were used with immobilized CD166. Human cord blood CD34 cells expressing CD166 produced significantly higher numbers of CFUs following interaction with immobilized CD166 than their CD166 counterparts. These data demonstrate the positive effects of CD166 homophilic interactions involving CD166 on the surface of murine and human HPCs. Single-cell RNA-seq analysis of CD150 CD48 (signaling lymphocyte activation molecule (SLAM)) LSK cells from WT and CD166 mice incubated with immobilized CD166 protein revealed that engagement of CD166 on these cells activates cytokine, growth factor and hormone signaling, epigenetic pathways, and other genes implicated in maintenance of stem cell pluripotency-related and mitochondria-related signaling pathways. These studies provide tangible evidence implicating CD166 engagement in the maintenance of stem/progenitor cell function. Stem Cells 2019;37:1319-1330.
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http://dx.doi.org/10.1002/stem.3053DOI Listing
October 2019

CP Tensor Decomposition with Cannot-Link Intermode Constraints.

Proc SIAM Int Conf Data Min 2019 May;2019:711-719

Emory University.

Tensor factorization is a methodology that is applied in a variety of fields, ranging from climate modeling to medical informatics. A tensor is an -way array that captures the relationship between objects. These multiway arrays can be factored to study the underlying bases present in the data. Two challenges arising in tensor factorization are 1) the resulting factors can be noisy and highly overlapping with one another and 2) they may not map to insights within a domain. However, incorporating supervision to increase the number of insightful factors can be costly in terms of the time and domain expertise necessary for gathering labels or domain-specific constraints. To meet these challenges, we introduce CANDECOMP/PARAFAC (CP) tensor factorization with Cannot-Link Intermode Constraints (CP-CLIC), a framework that achieves succinct, diverse, interpretable factors. This is accomplished by gradually learning constraints that are verified with auxiliary information during the decomposition process. We demonstrate CP-CLIC's potential to extract sparse, diverse, and interpretable factors through experiments on simulated data and a real-world application in medical informatics.
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http://dx.doi.org/10.1137/1.9781611975673.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563811PMC
May 2019

Phenotyping through Semi-Supervised Tensor Factorization (PSST).

AMIA Annu Symp Proc 2018 5;2018:564-573. Epub 2018 Dec 5.

Emory University, Atlanta, GA.

A computational phenotype is a set of clinically relevant and interesting characteristics that describe patients with a given condition. Various machine learning methods have been proposed to derive phenotypes in an automatic, high-throughput manner. Among these methods, computational phenotyping through tensor factorization has been shown to produce clinically interesting phenotypes. However, few of these methods incorporate auxiliary patient information into the phenotype derivation process. In this work, we introduce Phenotyping through Semi-Supervised Tensor Factorization (PSST), a method that leverages disease status knowledge about subsets of patients to generate computational phenotypes from tensors constructed from the electronic health records of patients. We demonstrate the potential of PSST to uncover predictive and clinically interesting computational phenotypes through case studies focusing on type-2 diabetes and resistant hypertension. PSST yields more discriminative phenotypes compared to the unsupervised methods and more meaningful phenotypes compared to a supervised method.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371355PMC
October 2019

Isolation and Identification of Murine Bone Marrow-Derived Macrophages and Osteomacs from Neonatal and Adult Mice.

Methods Mol Biol 2019 ;2002:181-193

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Hematopoietic stem cells (HSCs) are regulated by multiple components of the hematopoietic niche, including bone marrow-derived macrophages and osteomacs. However, both macrophages and osteomacs are phenotypically similar. Thus, specific phenotypic markers are required to differentially identify the effects of osteomacs and bone marrow macrophages on different physiological processes, including hematopoiesis and bone remodeling. Here, we describe a protocol for isolation of murine bone marrow-derived macrophages and osteomacs from neonatal and adult mice and subsequent identification by multi-parametric flow cytometry using an 8-color antibody panel.
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http://dx.doi.org/10.1007/7651_2018_196DOI Listing
March 2020

Bayesian Online Changepoint Detection Of Physiological Transitions.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:45-48

Transition dynamics between two states can help elucidate the behavior of sequential events in physiological signals. By detecting transitions between healthy and pathological states within individual patients, we can help clinicians focus attention on critical transitions, to either preemptively treat adverse events or to detect changes resulting from treatments. We introduce a novel application of singlepoint Bayesian online changepoint detection to predict clinical state transitions, and apply this framework to detecting pathological transitions in preterm infants with episodes of apnea and bradycardia. Bayesian analysis of sequential physiological events provides insights on how to objectively classify clinically important state transitions that can be triggered by external or intrinsic mechanisms.
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http://dx.doi.org/10.1109/EMBC.2018.8512204DOI Listing
July 2018

Metronomic therapy in metastatic castrate-resistant prostate cancer: Experience from a tertiary cancer care center.

Indian J Cancer 2018 Jan-Mar;55(1):94-97

Department of Medical Oncology, Tata Medical Center, Kolkata, West Bengal, India.

Background: Many agents have shown survival advantage in metastatic castrate-resistant prostate cancer (mCRPC). Despite this improvement, survival is poor, especially in subgroup of elderly patients who are not fit for cytotoxic chemotherapy.

Materials And Methods: This is a single-institutional data review of mCRPC treated between December 2012 and May 2016 with oral cyclophosphamide (50-100 mg/day) ± oral prednisolone. mCRPCs failed or not fit for docetaxel and/or abiraterone were included in this study. Monthly prostate-specific antigen (PSA) was monitored, and toxicity of cyclophosphamide was recorded. PSA response was defined as ≥50% reduction from precyclophosphamide value. The median follow-up was calculated from the day of starting cyclophosphamide and the last date of follow-up or death, whichever is later.

Results: Eighteen patients were included with a median age of 74.5 years (range: 59-83). The site of metastasis was bone in 15, bone and distant lymph nodes in 2, and rectum in 1 patient. The median duration of androgen deprivation was 21 months (range: 3-42.9 months). The median cyclophosphamide exposure was 2 months (range: 0.9-13.5 months) after a median follow-up of 5.8 months. Overall PSA response rate was 44%. The median PSA progression-free survival with cyclophosphamide was 4.7 months (range: 0.9-13.5 months). Five patients had durable PSA response of 9.9, 10.1, 10.5, 12.1, and 13.5 months, respectively. No Grade 3 or 4 toxicity was observed with cyclophosphamide.

Conclusion: Oral metronomic cyclophosphamide was found to be an effective and well-tolerated therapy in mCRPC after failure or not fit for docetaxel and/or abiraterone. In few patients, cyclophosphamide induced durable PSA response. This finding needs further evaluation in a prospective manner.
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http://dx.doi.org/10.4103/ijc.IJC_346_17DOI Listing
November 2018

Cisplatin-induced hearing loss in children with cancer.

Natl Med J India 2017 Nov-Dec;30(6):327-328

Department of Medical Oncology, Dr B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.

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http://dx.doi.org/10.4103/0970-258X.239073DOI Listing
October 2019

Metastatic Gastric cancer: Real world scenario from a developing country.

South Asian J Cancer 2018 Jul-Sep;7(3):171-174

Department of Medical Oncology, Tata Medical Center, Kolkata, West Bengal, India.

Aim: Data on epidemiology and outcome in metastatic stomach carcinoma patients from India are scarce. We aimed to evaluate clinical features and treatment outcome in patients treated at our center.

Materials And Methods: This is a single institutional review of metastatic gastric carcinoma patients treated between May 2011 and October 2016. Patients who received at least one cycle of chemotherapy were included for modified intent-to-treat survival analysis.

Results: total of 143 patients were diagnosed with metastatic stomach carcinoma with a median age of 56 years (range: 29-86). The most common symptoms were abdominal pain in 112 (78%) patients. The most common site was body in 81 (57%) patients. Common site of metastasis was peritoneum in 86 (60%) and liver in (62%). Seventy-one (50%) patients were eligible for survival analysis. Common chemotherapy regimens were capecitabine-cisplatin in 27 (38%) and EOX in 22 (31%) patients. Survival status could not be assessed in 29 (41%) patients who lost to follow-up. After a median follow-up 9.7 months (range: 0.5-37.7), median progression-free survival (PFS) was 7.9 months (range: 0.5-23.9) and median overall survival (OS) was 12.2 months (range: 0.5-37.7). The Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 and the presence of linitis plastica showed a trend toward inferior PFS ( = 0.052 and 0.053, respectively) only in univariate analysis. Female sex and ECOG PS ≥2 predicted inferior OS in both univariate and multivariate analysis ( = 0.012, 0.02 and 0.03 and 0.05, respectively).

Conclusions: Platinum-based doublet chemotherapy was used in the majority of patients. The overall outcome was comparable to that of the available literature. Female sex and ECOG PS ≥2 predicted the inferior outcome.
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http://dx.doi.org/10.4103/sajc.sajc_2_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069341PMC
August 2018

Phenotype Instance Verification and Evaluation Tool (PIVET): A Scaled Phenotype Evidence Generation Framework Using Web-Based Medical Literature.

J Med Internet Res 2018 05 4;20(5):e164. Epub 2018 May 4.

Northeastern University, Boston, MA, United States.

Background: Researchers are developing methods to automatically extract clinically relevant and useful patient characteristics from raw healthcare datasets. These characteristics, often capturing essential properties of patients with common medical conditions, are called computational phenotypes. Being generated by automated or semiautomated, data-driven methods, such potential phenotypes need to be validated as clinically meaningful (or not) before they are acceptable for use in decision making.

Objective: The objective of this study was to present Phenotype Instance Verification and Evaluation Tool (PIVET), a framework that uses co-occurrence analysis on an online corpus of publically available medical journal articles to build clinical relevance evidence sets for user-supplied phenotypes. PIVET adopts a conceptual framework similar to the pioneering prototype tool PheKnow-Cloud that was developed for the phenotype validation task. PIVET completely refactors each part of the PheKnow-Cloud pipeline to deliver vast improvements in speed without sacrificing the quality of the insights PheKnow-Cloud achieved.

Methods: PIVET leverages indexing in NoSQL databases to efficiently generate evidence sets. Specifically, PIVET uses a succinct representation of the phenotypes that corresponds to the index on the corpus database and an optimized co-occurrence algorithm inspired by the Aho-Corasick algorithm. We compare PIVET's phenotype representation with PheKnow-Cloud's by using PheKnow-Cloud's experimental setup. In PIVET's framework, we also introduce a statistical model trained on domain expert-verified phenotypes to automatically classify phenotypes as clinically relevant or not. Additionally, we show how the classification model can be used to examine user-supplied phenotypes in an online, rather than batch, manner.

Results: PIVET maintains the discriminative power of PheKnow-Cloud in terms of identifying clinically relevant phenotypes for the same corpus with which PheKnow-Cloud was originally developed, but PIVET's analysis is an order of magnitude faster than that of PheKnow-Cloud. Not only is PIVET much faster, it can be scaled to a larger corpus and still retain speed. We evaluated multiple classification models on top of the PIVET framework and found ridge regression to perform best, realizing an average F1 score of 0.91 when predicting clinically relevant phenotypes.

Conclusions: Our study shows that PIVET improves on the most notable existing computational tool for phenotype validation in terms of speed and automation and is comparable in terms of accuracy.
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http://dx.doi.org/10.2196/jmir.9610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960038PMC
May 2018

Resource requirements and reduction in cardiac mortality from deep inspiration breath hold (DIBH) radiation therapy for left sided breast cancer patients: A prospective service development analysis.

Pract Radiat Oncol 2018 Nov - Dec;8(6):382-387. Epub 2018 Mar 21.

Department of Surgical Oncology, Tata Medical Center, Newtown, Kolkata, West Bengal.

Introduction: Use of deep inspiration breath hold (DIBH) radiation therapy may reduce long-term cardiac mortality. The resource and time commitments associated with DIBH are impediments to its widespread adoption. We report the dosimetric benefits, workforce requirements, and potential reduction in cardiac mortality when DIBH is used for left-sided breast cancers.

Methods And Materials: Data regarding the time consumed for planning and treating 50 patients with left-sided breast cancer with DIBH and 20 patients treated with free breathing (FB) radiation therapy were compiled prospectively for all personnel (regarding person-hours [PH]). A second plan was generated for all DIBH patients in the FB planning scan, which was then compared with the DIBH plan. Mortality reduction from use of DIBH was calculated using the years of life lost resulting from ischemic heart disease for Indians and the postulated reduction in risk of major cardiac events resulting from reduced cardiac dose.

Results: The median reduction in mean heart dose between the DIBH and FB plans was 166.7 cGy (interquartile range, 62.7-257.4). An extra 6.76 PH were required when implementing DIBH as compared with FB treatments. Approximately 3.57 PH were necessary per Gy of reduction in mean heart dose. The excess years of life lost from ischemic heart disease if DIBH was not done in was 0.95 per 100 patients, which translates into a saving of 12.8 hours of life saved per PH of work required for implementing DIBH. DIBH was cost effective with cost for implementation of DIBH for all left-sided breast cancers at 2.3 times the annual per capita gross domestic product.

Conclusion: Although routine implementation of DIBH requires significant resource commitments, it seems to be worthwhile regarding the projected reductions in cardiac mortality.
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http://dx.doi.org/10.1016/j.prro.2018.03.007DOI Listing
January 2019

Osteomacs interact with megakaryocytes and osteoblasts to regulate murine hematopoietic stem cell function.

Blood Adv 2017 Dec 5;1(26):2520-2528. Epub 2017 Dec 5.

Department of Microbiology and Immunology.

Networking between hematopoietic stem cells (HSCs) and cells of the hematopoietic niche is critical for stem cell function and maintenance of the stem cell pool. We characterized calvariae-resident osteomacs (OMs) and their interaction with megakaryocytes to sustain HSC function and identified distinguishing properties between OMs and bone marrow (BM)-derived macrophages. OMs, identified as CD45F4/80 cells, were easily detectable (3%-5%) in neonatal calvarial cells. Coculture of neonatal calvarial cells with megakaryocytes for 7 days increased OM three- to sixfold, demonstrating that megakaryocytes regulate OM proliferation. OMs were required for the hematopoiesis-enhancing activity of osteoblasts, and this activity was augmented by megakaryocytes. Serial transplantation demonstrated that HSC repopulating potential was best maintained by in vitro cultures containing osteoblasts, OMs, and megakaryocytes. With or without megakaryocytes, BM-derived macrophages were unable to functionally substitute for neonatal calvarial cell-associated OMs. In addition, OMs differentiated into multinucleated, tartrate resistant acid phosphatase-positive osteoclasts capable of bone resorption. Nine-color flow cytometric analysis revealed that although BM-derived macrophages and OMs share many cell surface phenotypic similarities (CD45, F4/80, CD68, CD11b, Mac2, and Gr-1), only a subgroup of OMs coexpressed M-CSFR and CD166, thus providing a unique profile for OMs. CD169 was expressed by both OMs and BM-derived macrophages and therefore was not a distinguishing marker between these 2 cell types. These results demonstrate that OMs support HSC function and illustrate that megakaryocytes significantly augment the synergistic activity of osteoblasts and OMs. Furthermore, this report establishes for the first time that the crosstalk between OMs, osteoblasts, and megakaryocytes is a novel network supporting HSC function.
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http://dx.doi.org/10.1182/bloodadvances.2017011304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728639PMC
December 2017

Tamm-Horsfall Protein Regulates Mononuclear Phagocytes in the Kidney.

J Am Soc Nephrol 2018 03 27;29(3):841-856. Epub 2017 Nov 27.

Departments of Medicine,

Tamm-Horsfall protein (THP), also known as uromodulin, is a kidney-specific protein produced by cells of the thick ascending limb of the loop of Henle. Although predominantly secreted apically into the urine, where it becomes highly polymerized, THP is also released basolaterally, toward the interstitium and circulation, to inhibit tubular inflammatory signaling. Whether, through this latter route, THP can also regulate the function of renal interstitial mononuclear phagocytes (MPCs) remains unclear, however. Here, we show that THP is primarily in a monomeric form in human serum. Compared with wild-type mice, THP mice had markedly fewer MPCs in the kidney. A nonpolymerizing, truncated form of THP stimulated the proliferation of human macrophage cells in culture and partially restored the number of kidney MPCs when administered to THP mice. Furthermore, resident renal MPCs had impaired phagocytic activity in the absence of THP. After ischemia-reperfusion injury, THP mice, compared with wild-type mice, exhibited aggravated injury and an impaired transition of renal macrophages toward an M2 healing phenotype. However, treatment of THP mice with truncated THP after ischemia-reperfusion injury mitigated the worsening of AKI. Taken together, our data suggest that interstitial THP positively regulates mononuclear phagocyte number, plasticity, and phagocytic activity. In addition to the effect of THP on the epithelium and granulopoiesis, this new immunomodulatory role could explain the protection conferred by THP during AKI.
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http://dx.doi.org/10.1681/ASN.2017040409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827593PMC
March 2018

gamAID: Greedy CP tensor decomposition for supervised EHR-based disease trajectory differentiation.

Annu Int Conf IEEE Eng Med Biol Soc 2017 Jul;2017:3644-3647

We propose gamAID, an exploratory, supervised nonnegative tensor factorization method that iteratively extracts phenotypes from tensors constructed from medical count data. Using data from diabetic patients who later on get diagnosed with chronic kidney disorder (CKD) as well as diabetic patients who do not receive a CKD diagnosis, we demonstrate the potential of gamAID to discover phenotypes that characterize patients who are at risk for developing a disease.
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http://dx.doi.org/10.1109/EMBC.2017.8037647DOI Listing
July 2017

The obesity paradox in ICU patients.

Annu Int Conf IEEE Eng Med Biol Soc 2017 Jul;2017:3360-3364

Excessive weight is connected with an increased risk of certain life-threatening diseases. However, some evidence shows that among patients with chronic diseases such as heart failure (HF) chronic kidney disease (CKD) and COPD, increased weight is paradoxically associated with a decreased risk of mortality. This counterintuitive phenomenon is referred to as the obesity paradox. The obesity paradox has been mostly observed among certain cohorts of patients with HF, but not specific to patients in the Intensive Care Unit (ICU) setting. This paper studies the relationship between obesity and mortality of ICU patients with and without HF and presents evidence supporting the existence of this paradox. The results provide helpful insights for developing more patient-centric care in ICUs. Additionally, we use both the MIMIC-II and (recently available) MIMIC-III databases, for which few comparative studies exist to date. We demonstrate an aspect of consistency between the databases, providing a significant step towards validating the use of the newly announced MIMIC-III in broader studies.
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http://dx.doi.org/10.1109/EMBC.2017.8037576DOI Listing
July 2017

PheKnow-Cloud: A Tool for Evaluating High-Throughput Phenotype Candidates using Online Medical Literature.

AMIA Jt Summits Transl Sci Proc 2017 26;2017:149-157. Epub 2017 Jul 26.

The University of Texas at Austin, Austin, TX.

As the adoption of Electronic Healthcare Records has grown, the need to transform manual processes that extract and characterize medical data into automatic and high-throughput processes has also grown. Recently, researchers have tackled the problem of automatically extracting candidate phenotypes from EHR data. Since these phenotypes are usually generated using unsupervised or semi-supervised methods, it is necessary to examine and validate the clinical relevance of the generated "candidate" phenotypes. We present PheKnow-Cloud, a framework that uses co-occurrence analysis on the publicly available, online repository ofjournal articles, PubMed, to build sets of evidence for user-supplied candidate phenotypes. PheKnow-Cloud works in an interactive manner to present the results of the candidate phenotype analysis. This tool seeks to help researchers and clinical professionals evaluate the automatically generated phenotypes so they may tune their processes and understand the candidate phenotypes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543339PMC
July 2017

Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: Is There Sufficient Evidence?

J Clin Oncol 2017 06 4;35(18):2095-2096. Epub 2017 May 4.

Bivas Biswas, Sandip Ganguly, Joydeep Ghosh, Prasad E, and Deepak Dabkara, Tata Medical Center, Kolkata, India.

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http://dx.doi.org/10.1200/JCO.2017.72.8600DOI Listing
June 2017

Role of mTORC1-S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia.

Exp Hematol 2017 06 22;50:13-21. Epub 2017 Mar 22.

Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address:

Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-p70 ribosomal protein kinase 1 (S6K1) signaling pathway occurs frequently in acute myeloid leukemia (AML) patients. This pathway also plays a critical role in maintaining normal cellular processes. Given the importance of leukemia stem cells (LSCs) in the development of minimal residual disease, it is critical to use therapeutic interventions that target the LSC population to prevent disease relapse. The mTORC1-S6K1 pathway has been identified as an important regulator of hematopoietic stem cell (HSC) and LSC functions. Both HSC and LSC functions require regulation of key cellular processes including proliferation, metabolism, and autophagy, which are regulated by mTORC1 pathway. Despite the mTORC1-S6K1 pathway being a critical regulator of AML initiation and progression, inhibitors of this pathway alone have yielded mixed results in clinical studies. Recent studies have identified strategies to develop new mTORC1-S6K1 inhibitors such as RapaLink-1, which could circumvent the drug resistance observed in AML cells and in LSCs. Here, we review recent advances made in identifying the role of different components of this pathway in the regulation of HSCs and LSCs and discuss possible therapeutic approaches.
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http://dx.doi.org/10.1016/j.exphem.2017.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569945PMC
June 2017

Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma in the Era of Targeted Therapy: Scientifically Relevant or Natural Selection?

J Clin Oncol 2017 04 6;35(11):1265-1266. Epub 2017 Feb 6.

Bivas Biswas, Deepak Dabkara, Sandip Ganguly, Prasad Eswaran, and Joydeep Ghosh, Tata Medical Center, New Town, Rajarhat, Kolkata, India.

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http://dx.doi.org/10.1200/JCO.2016.70.8156DOI Listing
April 2017

Neoadjuvant imatinib: longer the better, need to modify risk stratification for adjuvant imatinib.

J Gastrointest Oncol 2016 Aug;7(4):624-31

Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.

Background: Multimodality treatment of gastrointestinal stromal tumor (GIST) with surgery and adjuvant imatinib mesylate (IM), along with an emerging role for neoadjuvant IM prior to evaluation for resectability has resulted in high survival rates.

Methods: We conducted a retrospective analysis of prospectively collected data of patients who underwent surgery for GIST, prior to or followed by IM therapy. A total of 112 patients underwent surgery between January 2009 and March 2015 at our centre. This included 27 patients with upfront resectable disease, 76 patients with locally advanced GIST who received neoadjuvant IM followed by surgery and 9 patients with metastatic disease who had excellent response to IM and were taken for surgery.

Results: The primary tumor in the non metastatic patients was in the stomach (53%), duodenum (16%), rectum (12%), jejunum (11%), ileum (7%), and others (2%). Median duration of neoadjuvant IM was 5 months with 4 patients showing disease progression during neoadjuvant IM. Ninety-three percent of all patients had R0 resections, while 7% had R+ resections. The estimated 3- and 5-year DFS in non-metastatic patients was 86.1% and 67% respectively with a 3- and 5-year median OS of 95.4% and 91.7% respectively. Five-year PFS and OS for the metastatic patients was 88.8% and 100% respectively. Lack of adjuvant IM was the only factor related to inferior PFS and OS.

Conclusions: Longer duration of neoadjuvant IM should be considered in locally advanced GIST prior to surgery and resection may be considered in responding metastatic patients.
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http://dx.doi.org/10.21037/jgo.2016.03.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963379PMC
August 2016

S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance.

J Clin Invest 2016 07 13;126(7):2621-5. Epub 2016 Jun 13.

Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) functions and promotes leukemogenesis. mTORC1 and mTORC2 differentially control normal and leukemic stem cell functions. mTORC1 regulates p70 ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding (eIF4E-binding) protein 1 (4E-BP1), and mTORC2 modulates AKT activation. Given the extensive crosstalk that occurs between mTORC1 and mTORC2 signaling pathways, we assessed the role of the mTORC1 substrate S6K1 in the regulation of both normal HSC functions and in leukemogenesis driven by the mixed lineage leukemia (MLL) fusion oncogene MLL-AF9. We demonstrated that S6K1 deficiency impairs self-renewal of murine HSCs by reducing p21 expression. Loss of S6K1 also improved survival in mice transplanted with MLL-AF9-positive leukemic stem cells by modulating AKT and 4E-BP1 phosphorylation. Taken together, these results suggest that S6K1 acts through multiple targets of the mTOR pathway to promote self-renewal and leukemia progression. Given the recent interest in S6K1 as a potential therapeutic target in cancer, our results further support targeting this molecule as a potential strategy for treatment of myeloid malignancies.
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http://dx.doi.org/10.1172/JCI84565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922705PMC
July 2016

A cross-sectional observation study regarding patients and their physician willingness to wait for driver mutation report in nonsmall-cell lung cancer.

Indian J Med Paediatr Oncol 2016 Apr-Jun;37(2):74-8

Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.

Background: Palliative chemotherapy +/- targeted therapy in accordance with mutation profile is the norm in nonsmall-cell lung cancer (NSCLC). The objective of this audit was to determine the proportion of patients and physicians, who are unwilling to wait for the mutation report and the reasons thereof.

Materials And Methods: All newly diagnosed NSCLC patients, post biopsy, seen at our center between November 2014 and January 2015 were included. The relationship between patient and physician decision and objective factors was explored by Fisher's exact test. The factors considered were Eastern Cooperative Oncology Group performance status (ECOG PS), the presence of a cough, hemoptysis, fatigue, and breathlessness. The agreement between patients and physician decision was tested by contingency table.

Results: Out of 168 patients, 57 were unwilling to wait for driver mutation report (33.9% 95% confidence interval [CI] 27.2-41.4%). The most common reason provided by patients was symptomatic status (23, 40.1%). No other objective factor except PS (P = 0.00) was associated with patient's decision. In 56 patients (33.4% 95% CI 26.6-40.7%), physicians were unwilling to wait. Among the tested factors ECOG PS (P = 0.000), breathlessness (P = 0.00) and fatigue (P = 0.00) were associated with the decision of not waiting for the report. The percentage corrected value of contingency between patients and physician decision was 78.74%.

Conclusion: At present, in our setup, nearly one-third of our NSCLC patients opt for immediate chemotherapy treatment and are unwilling to wait for mutation analysis report. The major reasons for such attitude is poor symptom control and deteriorating general condition.
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http://dx.doi.org/10.4103/0971-5851.180138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854050PMC
May 2016